The broad objective of this research program is to gain understanding of the nature of diabetes mellitus in humans, particularly with regard to etiology, and to mechanisms of physiological, cellular, biochemical and molecular changes. The proposed approach to the pathology of human diabetes mellitus focuses on four major interrelated general areas: (1) the pathogenesis of insulin- dependent diabetes mellitus (IDDM); (2) molecular and functional abnormalities of lipoprotein lipase; (3) the pathogenesis of atherosclerosis in diabetes; and (4) development of a genetic rodent model linking diabetes and atherosclerosis susceptibility. Projects are proposed to study the effect of immune-mediated beta cell destruction on functional tests of insulin secretion in the preclinical phase of IDDM; regulation of lipoprotein lipase synthesis, secretion and action in diabetes; immune factors influencing the IDDM disease process; the regulation of cholesterol trafficking in arterial cells in diabetes; lipoprotein modification and metabolism by macrophages in diabetes; plasma lipoprotein abnormalities in diabetes; and the development of an animal model of diabetes and atherosclerosis. These projects are supported by a Microchemistry and Molecular Biology Core and an Administrative Core. This focus on basic biological mechanisms of abnormal cell function in diabetes should help establish which alterations are preventable or reversible and provide a rational basis for diagnosis and management of diabetes.